Update on the Closed-Loop Artificial Pancreas Project Stuart A Weinzimer, MD Associate Professor of...
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Transcript of Update on the Closed-Loop Artificial Pancreas Project Stuart A Weinzimer, MD Associate Professor of...
Update on the Closed-Loop Artificial Pancreas Project
Stuart A Weinzimer, MD
Associate Professor of Pediatrics
Yale University School of Medicine
CWD Friends For Life 7 July 2011
Rationale for a Closed-Loop System
• Present methods of diabetes treatment improve, but don’t normalize, blood glucose levels, even with CGM
• Burden of care extremely high
• CL would advance our ability to control BG levels while at the same time REDUCE burden on user
JDRF- and NIH-funded Closed-Loop Control AP Research
Yale
Jaeb Center
Mayo
JDRF & NIH fundingJDRF funding NIH funding
UCSB/Sansum
Benaroya
Oregon
Stanford
ColoradoVirginia
Boston
Cambridge
MontpellierPavia/Padova
Israel
UCSDRensselaer
W. OntarioW. Australia
Potential Pathway to an Artificial Pancreas
Medtronic ePID closed-loop system
• Paradigm 715 insulin pump• MMT sensor adapted for one-minute transmission• Laptop computer with software program and algorithm
PID algorithm components
0 60 120 1800
1
2
3
dt
tdGKtD D
)()(
0 60 120 1800
1
2
3
)()( BP GGKtP
Ins
ulin
(U/h
)
0 60 120 1800
1
2
3
dtGGKtI BI )()(
0 60 120 1800
2
4
6
TIME (min)
Insu
lin
(U
/h)
• Proportional – to the glucose level• Integral – slowly adaptive to normalize glucose• Derivative – rate-of-change of the glucose
Steil GM, et al. Diabetes Technol Ther. 2003;5:953-64.
Late post-prandial hypoglycemia in CL
6 12 18 24 30 36 420
3
6
9
12
15
18
0
50
100
150
Plasma InsulinEVP
Insu
lin
(U
/h)
Insu
lin (
U/m
l)
6 12 18 24 30 36 420
100
200
300
0
25
50
SG CHO
Glu
cose
(m
g/d
l)
Hybrid control improves performance
6A Noon 6P MidN 6A Noon 6P0
100
200
300Closed Loop (N=8)
meals
setpoint
Hybrid CL (N=9)
Glu
cose
(m
g/d
l)
Mean Daytime Peak PP
Full CL 147 58 154 60 219 54
Hybrid 138 49 143 50 196 52
Weinzimer SA. Diabetes Care 2008; 31:934-939.
Conclusions of study
• CL control feasible in youth with T1D
• Manual insulin “priming bolus” improved meal excursions
• Tendency to late post-prandial hypoglycemia
• Limitations– No OL control– Subjects were sedentary
Effect of daytime exercise on risk of subsequent nocturnal hypoglycemia
0
10
20
30
40
50
60
Su
bje
cts
(%)
Sedentary Exercise
28 %
48 %
- DirecNet, J Pediatr 2005; DirecNet, Pediatr Diabetes 2007
Study objective
• To evaluate whether use of a CL system reduces the risk of delayed (nocturnal) hypoglycemia following antecedent daytime exercise
Study Protocol
• 12 subjects admitted to Inpatient HRU on two separate occasions: routine pump therapy (OL) or sensor-driven pump therapy (CL)
• Two 24-h evaluation periods: 8AM d#2 - 8AM d#4
• Meals in both conditions are provided at 8AM, noon, and 5PM. Subjects consume identical meals under both conditions.
• Manual pre-meal bolus given (0.05 units/kg)
• Hypoglycemia 60 mg/dL (3.3 mmol)
Exercise Protocol
• One 1 of the 2 study days
• Treadmill walking to target HR for 15 min x 4, followed by 5 min rest
• Supplemental CHO to give boost starting BG>120 mg/dL (6.7 mmol)
Blood Glucose (mg/dL)
Fre
qu
ency
(%
)
0 40 80 120 160 200 240 280 3200.00
0.05
0.10
0.15
0.20
0.25 CL-Sed
OL-Sed
Glucose Histogram – Night after sedentary
2 % 97 % 1 %
5 % 86 % 9 %
p=0.02
Blood Glucose (mg/dL)
Fre
qu
ency
(%
)
0 40 80 120 160 200 240 280 3200.00
0.05
0.10
0.15
0.20
CL-Ex
OL-Ex
Glucose Histogram – Night after Exercise
6 % 90 % 4 %
11 % 72 % 17 %
p=0.003
Nocturnal Hypoglycemia
Closed LoopOpen Loop
0
5
10
15
20
25
3
22
All Nocturnal Hypo
Nu
mb
er
of
Tre
atm
en
ts G
iven
p=0.05
1
14
Night Following Exercise
p=0.06
Summary and Conclusions
• CL control was associated with:– Greater time within target range at night compared
to OL for both sedentary and exercise days– Fewer episodes of frank hypoglycemia
• Use of a CL, even if only at night, may be effective in reducing hypoglycemia
• Prandial glycemic excursions still undesirable
Next study questions
• Can the addition of pramlintide improve the performance of a CL system by reducing the peak post-prandial glucose excursions?
Pramlintide
• Analog of human amylin
• Co-secreted with insulin from -cell
• Used as adjunct to insulin in T1D to reduce post-prandial glycemic excursions
– Delay gastric emptying– Suppress endogenous glucagon
Study Protocol
• 8 subjects admitted to Inpatient HRU for CL control
• Two 24-h evaluation periods: 8AM d#2 - 8AM d#4
• Meals provided at 8AM, 1PM, and 6PM. Subjects consume identical meals under both conditions.
• Pramlintide 30 mcg given prior to each meal on one study day
• Hypoglycemia 60 mg/dL (3.3 mmol)
Glucose excursions with/without pramlintide
6 9 12 15 18 21 24 27 30 330
100
200
300
Control Day
Symlin Day
Time (hrs)
Blo
od
G
luco
se (
mg
/dL
)
Pramlintide reduced peak post-prandial BG
Breakfast Lunch Dinner0
50
100
150Pramlintide
Control
BG
exc
urs
ion
(m
g/d
l)
*p=0.03
*
Adverse Effects
Hypoglycemia
• No BG < 60 (3.3)
• <70 (3.9)
Pramlintide (2%)
Control (1%)
Gastrointestinal
None !
Summary and conclusions
• Pramlintide had modest effect on prandial glucose
• Would require manual injection or at best, manual bolus
• Faster insulin absorption / action clearly needed
Next Steps
• Evaluation of other incretins
• Strategies to accelerate insulin absorption / action
InsuPatch infusion site warming device
• Heating element that adheres to an insulin pump catheter site
• Warms skin to 38-39°C
• Activated manually or automatically with insulin bolus
• Putative accelerates insulin absorption through increased local blood flow
Effect of InsuPatch on Insulin Action
0 60 120 180 240 3000.0
2.0
4.0
6.0
8.0
Time (min)
GIR
(m
g/k
g/m
in)
No InsuPatchWith InsuPatch
Cengiz, DTS Meeting 2010
(n=8)No
InsuPatchWith
InsuPatch
GIR0-90min 2.4 ± 1 3.7 ± 2
Tmax GIR (min) 133 ± 27 84 ± 18
T early 50% (min) 66 ± 16 41 ± 15
AUC GIR 0-90min 226 ± 100 343 ± 141
Effect of InsuPatch on meals
Cengiz, unpublished
Baseline +30 +60 +90 +120 +150 +180 +210 +240-20
0
20
40
60
80
With InsuPatch
Without InsuPatch
Time (min)
Ch
ang
e in
B
G f
rom
Bas
elin
e (
mg
/dl) (n=9)
Other approaches to AP
• “Control to Range” – OL when BGs within target– Automatic pump suspension for actual or
predicted hypoglycemia– Pump augmentation for hyperglycemia
CL2-MW 9/3/08
Time in Minutes Beginning at 9:30 PM
0 100 200 300 400 500 600
Ser
um G
luco
se (
mg/
dl)
20
40
60
80
100
120
140
160
Y A
xis
2
0.0
0.5
1.0
1.5
2.0
Controller GlucoseYSI Basal Insulin
ROC = -.36 mg/dl-min3 Alarm, Threshold 80 mg/dl, Horizon 35 minAutomatic pump suspension for predicted hypoglycemia
The take-home message
• Pumps and sensors are becoming increasingly integrated and automated, but self-care burden is still high
• Full CL delivery is possible with current technologies but will likely require manual interfaces to completely optimize BG control
• Dual hormonal control will improve performance of CL systems but will add additional regulatory complexity
• Path to a true product will be iterative
Thank you!
• Yale Closed Loop Team– Stu Weinzimer– Jennifer Sherr– Eda Cengiz– William Tamborlane– Grace Kim– Lori Carria– Amy Steffen– Kate Weyman– Melinda Zgorski